e importance of the lysosomal enzyme, Beta-hexosaminidase, is illustrated Tay-Sachs and Sandhoff diseases which are caused by mutations in the zyme's Alpha and Beta chains, respectively. Previously, we had aracterized the normal biosynthetic pathway of the enzyme and the sruption of this pathway in patients with Tay-Sachs disease. In order to vestigate both normal and abnormal aspects of the enzyme at the DNA level, had cloned a cDNA corresponding to the Alpha-chain. Using Alpha-chain NA probes I have screened human genomic libraries constructed in cosmid and cteriophage lambda vectors and have isolated several clones containing the ne for the Alpha-chain. These clones are being extensively characterized restriction mapping, Southern blotting and DNA sequencing. Thus far, the tron-exon organization of 75% of the 20 kilobase Alpha-chain gene has been termined. This work will provide the informational framework for the entual elucidation of mutations in Tay-Sachs disease. In addition, the aracterization of this first lysosomal enzyme gene may provide novel sight into this important class of cellular glycoproteins.